Alzheimer's disease afflicts an estimated 5.1 million people in the United States, and as life expectancies increase it is anticipated that this number will continue to rise (Institute of Medicine, 2008). Besides the personal toll on the patients and their caregivers (who often are family members), the cost of caring for those with dementia is anticipated to grow from the 2011 estimate of $187 billion to $1.1 trillion by the year 2050. Currently the most widely accepted automated method for measurement of the hippocampus in Alzheimer's disease is FreeSurfer. At Brain Image Analysis, LLC we have processed the MRI data from the ADNI 1 dataset (>3500 scans) using our automated pipeline, BRAINS AutoWorkup. In our analysis have found that, in comparisons with both the standard FreeSurfer and the longitudinal stream in FreeSurfer, our methods detect a higher annual atrophy rate with a lower relative standard deviation. This leads to a substantial reduction in the estimates of subjects needed per arm of a clinical trial from 131 or 204 using FreeSurfer (longitudinal and cross-sectional workflows) to 56 using BRAINS ANN methods. This application describes how we intend to implement and test a longitudinal ANN method and test our current hippocampal segmentations against those being prepared by a collaboration of Alzheimer's disease researchers and hippocampus experts. This will provide Brain Image Analysis, LLC with the information it needs to show our methods of subcortical segmentation are the most feasible in the field for commercial image processing in the study of Alzheimer's disease and its treatment. Phase II of this project will encompass implementation of these methods into the newest version of BRAINS and the additional program infrastructure to make our methods available on a larger commercial scale, as well as implementation on a large dataset to explore clinical correlates. Working with us on this project will be renowned neuroscience researchers. These include Dr. Vincent Magnotta and Dr. Nancy Andreasen, long-term leaders of development team for BRAINS, and Dr. Doug Langbehn, serving as our statistician with substantial experience in large imaging studies designed to support clinical trials.